Palladium-Catalyzed Chlorocarbonylation of Aryl (Pseudo)Halides Through In Situ Generation of Carbon Monoxide

Article abstract of DOI:10.1002/anie.202005891

An efficient palladium-catalyzed chlorocarbonylation of aryl (pseudo)halides that gives access to a wide range of carboxylic acid derivatives has been developed. The use of butyryl chloride as a combined CO and Cl source eludes the need for toxic, gaseous carbon monoxide, thus facilitating the synthesis of high-value products from readily available aryl (pseudo)halides. The combination of palladium(0), Xantphos, and an amine base is essential to promote this broadly applicable catalytic reaction. Overall, this reaction provides access to a great variety of carbonyl-containing products through in situ transformation of the generated aroyl chloride. Combined experimental and computational studies support a reaction mechanism involving in situ generation of CO.

Full text of DOI:10.1002/anie.202005891

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Palladium-catalyzed Chlorocarbonylation of Aryl (pseudo)Halides
through in situ Generation of Carbon Monoxide
Authors: Philip Boehm, Sven Roediger, Alessandro Bismuto, and Bill
Morandi
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10.1002/anie.202005891
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RESEARCH ARTICLE
Palladium-catalyzed Chlorocarbonylation of Aryl (pseudo)Halides
through in situ Generation of Carbon Monoxide
Philip Boehm, Sven Roediger, Alessandro Bismuto and Bill Morandi*
Dedication ((optional))
*
Philip Boehm, Sven Roediger, Dr. Alessandro Bismuto and Prof. Dr. Bill Morandi
Laboratorium für Organische Chemie, ETH Zürich
Vladimir-Prelog-Weg 3, HCI, 8093 Zürich, Switzerland
E-mail: bill.morandi@org.chem.ethz.ch
Supporting information for this article is given via a link at the end of the document.
Abstract: An efficient palladium-catalyzed chlorocarbonylation of aryl
(pseudo)halides to access a wide range of carboxylic acid derivatives
has been developed. The use of butyryl chloride as a combined CO
and Cl source eludes the need for toxic, gaseous carbon monoxide,
thus facilitating the synthesis of high-value products from readily
available aryl (pseudo)halides. The combination of palladium(0),
Xantphos, and an amine base is essential to promote this broadly
applicable catalytic reaction. Overall, this reaction provides access to
a great variety of carbonyl-containing products through in situ
transformation of the generated aroyl chloride. Combined
reactor.[10] Still, some synthetically relevant carbonyl compounds
remain challenging to access through transition metal-catalyzed
carbonylation chemistry, mainly due to the intrinsic low reactivity
of the corresponding nucleophiles. For instance, there is only one
report, where unactivated arenes could be employed as
nucleophiles in an intermolecular Friedel-Crafts type
carbonylation of aryl iodides.[11] In addition, the broad spectrum of
available catalytic systems for the carbonylation of aryl halides
also brings along the necessity to employ tailor-made catalysts for
each nucleophile or two catalyst systems as in the case of
Skrydstrup.[3,9,10] These drawbacks can limit the flexibility of this
strategy in target-oriented synthesis.
experimental and computational studies support
a
reaction
mechanism involving in situ generation of CO.
Introduction
Transition-metal catalysis is an important tool for the
efficient refinement of readily available chemical feedstocks into
more functionalized products. Among those, carboxylic acid
derivatives, aldehydes, and ketones are key intermediates often
found in the syntheses of pharmaceuticals, agrochemicals, and
other industrially relevant products.[1] An important route to access
these products is the carbonylation of aryl halides. Since the
seminal report from Heck and co-workers in 1974,[2] palladium-
catalyzed carbonylation of aromatic halides has seen tremendous
development.[1a,3] Most strategies make use of carbon monoxide
as the carbonyl source in the presence of an appropriate
nucleophile, e. g. alcohols, amines, thiols or organometallic
species, for alkoxycarbonylation,[3,4] aminocarbonylation,[3,5]
carbonylative Heck,[3,6] carbonylative Suzuki-Miyaura,[3,7] and
carbonylative Sonogashira.[3,8]
Scheme 1. Context of this work.
However, due to the high toxicity and gaseous nature of
carbon monoxide, the application of catalytic carbonylation
reactions on a laboratory scale remains underdeveloped. These
drawbacks can be overcome by the use of CO surrogates, such
as formaldehyde, alkyl formates, formic anhydride, formamides,
chloroform, aldehydes, or metal carbonyls.[9] Alternatively, an
elegant solution developed by Skrydstrup and co-workers can be
employed to generate CO ex situ in a two-chamber reactor, by-
passing the storage and manipulation of exogenous CO. By using
an acid chloride in one chamber of the reactor that can release
CO under palladium catalysis, a great variety of carbonylation
reactions can be performed in the second chamber of the
To bypass these limitations and develop an operationally
simple and unifying approach to access carbonyl containing
products from aryl (pseudo)halides, the formation and in situ
derivatization of aroyl chlorides presents an attractive alternative.
Acid chlorides are highly versatile intermediates in organic
synthesis and provide a platform for a wide range of subsequent
transformations. Reactions of acid chlorides include formation of
esters, amides, or ketones, as well as metal-catalyzed cross-
coupling reactions[12] and peptide-couplings[13] amongst others.[14]
Recently, Arndtsen and co-workers have shown the
chlorocarbonylation of aryl iodides and bromides using
1
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RESEARCH ARTICLE
pressurized carbon monoxide and a soluble chloride source
(Scheme 1a).[15]
add into the weaker acyl C-Cl bond of both starting material and
product.[15b,21] Inverting the stoichiometry of the reagents
completely shuts down the reaction (entry 4). Changing the
Pd2(dba)3 precatalyst to other Pd(0) sources gave a lower yield of
the desired aroyl chloride (entry 5). Reactions conducted with
decreased catalyst loading (entry 6) or temperature (entry 7)
resulted in lower yield. Toluene emerged as the best solvent for
this reaction (entry 8).[20]
Arndtsen and our group independently developed a single-bond
metathesis approach for the synthesis of acid chlorides from aryl
iodides, preventing the use of toxic, gaseous carbon monoxide
(Scheme 1b).[16] Still, the conversion of less expensive aryl
bromides and more readily available aryl triflates into the
corresponding acyl chlorides could not be achieved, leaving this
synthetic challenge unmet. Furthermore, the formation of
stoichiometric amounts of aryl iodide byproduct were interfering
with the purification of the acid chloride (vide infra).
Table 1. Optimization of reaction conditions for aryl bromides.[a]
In order to broaden the scope of the chlorocarbonylation and
address the recurring purification issues, we reasoned that the
use of butyryl chloride as an inexpensive CO and Cl source could
be very attractive. Our group previously reported the use of this
reagent, in a shuttle catalysis strategy,[17] as a source of HCl and
CO in a hydrochlorocarbonylation of alkynes and alkenes.[18] We
hypothesized that, in the presence of a base, we might divert this
reaction mechanism to facilitate the chlorocarbonylation of aryl
halides. A major benefit of this approach would be the release of
a volatile by-product, propene, thus facilitating the purification of
the final product. However, a major challenge in realizing this
reaction, or any reaction involving two distinct electrophiles,[19] is
to identify a suitable catalyst system which can mediate the
oxidative addition of the two respective electrophiles with a similar
rate to enable catalytic turnover.
Entry
1
Deviations from above
Yield [%][b]
none
25
18
2
2
PtBu3 instead of Xantphos
BrettPhos instead of Xantphos
3.0 equiv. of butyryl chloride
10 mol% Pd(PPh3)4 instead of Pd2(dba)3
2.5 mol% Pd2(dba)3, 5 mol% Xantphos
80 °C instead of 100 °C
3
4
traces
18
20
10
23
8
5
6
7
8
1,4-dioxane instead of toluene
2.0 equiv. of NEt3 instead of DIPEA
2.0 equiv. of K3PO4 instead of DIPEA
3.0 equiv. of DIPEA
Herein, we report
a
general palladium-catalyzed
9
chlorocarbonylation of aryl bromides, aryl iodides, and aryl
triflates, using butyryl chloride as CO/Cl-donor in the presence of
a base. We also provide key mechanistic and computational
results, which lay down the groundwork for the development of
new carbonylation reactions.
10
11
12
-
31
83[c]
3.0 equiv. of bromobenzene
[a] Reaction conditions: 1a (0.25 mmol), 2 (0.25 mmol), Pd2(dba)3 (5 mol%),
Xantphos (10 mol%), DIPEA (2.0 equiv.), toluene (1.25 mL) at 100 °C, 16 h. [b]
GC yield of the corresponding methyl ester using n-dodecane as internal
standard. [c] 3.0 equiv. DIPEA used.
Results and Discussion
Chlorocarbonylation of Aryl Bromides and Aryl Triflates.
With these optimized reaction conditions in hand, we moved
on to explore the substrate scope of the chlorocarbonylation of
aryl (pseudo)halides which could not be used as electrophiles in
previous examples of CO-free chlorocarbonylation.[16] Starting
with aryl bromides, a wide variety of aroyl chlorides could be
successfully accessed through this methodology (Table 2).
Indeed, aryl bromides bearing either electron-neutral (3a and 3d),
electron-rich (3b, 3i, and 3r), or electron-poor (3c, 3g, 3h, 3j, 3k,
3l, 3m, and 3n) substituents were tolerated under the reaction
conditions, giving the desired aroyl chlorides in good yield. The
chlorocarbonylation proved to be efficient in the presence of
heterocyclic compounds, such as pyridine, quinoline, benzofuran,
or benzothiophene (3o, 3p, 3q, and 3s). Notably, a styrene
derivative was tolerated under the reaction conditions, giving 3f in
62% yield. No Heck-type reaction was observed with this
substrate. A more complex flavone starting material was
converted efficiently into the corresponding acid chloride product
3t in 72% yield. Similar to earlier reports of palladium-catalyzed
chlorocarbonylations,[15a,b,16] substrates with ortho-substituents
resulted in poor conversions. The ortho-fluorine-substituted
product 3e was nonetheless obtained in 63% yield.
Evaluation of Reaction Conditions.
We began our investigations with bromobenzene (1a) and
butyryl chloride (2) as benchmark substrates (Table 1). In a
preliminary screening of monodentate and bidentate phosphines,
as well as different Pd(0) sources, a first hit with Pd2(dba)3 and
Xantphos was observed. After extensive evaluation of the
reaction conditions, we found that a combination of Pd2(dba)3,
Xantphos, and N,N-diisopropylethylamine (DIPEA) as a non-
nucleophilic, sterically encumbered base in toluene at 100 °C
gave the best result after a reaction time of 16 hours (see
Supporting Information, Tables S1-S11). Amongst the aliphatic
acid chlorides tested, butyryl chloride showed the highest
yields.[20] The bidentate ligand Xantphos proved to be superior to
all other tested ligands (entries 2 and 3), including sterically
encumbered trialkylphosphines that showed good reactivity in
prior examples of chlorocarbonylation.[15a,b] Other (amine) bases
had a deleterious effect on the reaction outcome (entry 9 and 10).
Since it is presumed that the reaction proceeds via the oxidative
addition of Pd(0) into both butyryl chloride and aryl halide (vide
infra), the rates of both processes have to match to avoid
accumulation of one reaction intermediate.[19] By using 3
equivalents of bromobenzene, the relative reaction rates can be
balanced, driving the reaction to high conversion and increasing
the yield drastically (entry 12). The excess of aryl bromide is
potentially required due to the preference of Pd(0) to oxidatively
2
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Table 2. Palladium-catalyzed chlorocarbonylation of aryl bromides.[a]
Table 3. Palladium-catalyzed chlorocarbonylation of aryl triflates.[a]
[a] Yields refer to isolated products after in situ derivatization of the labile acid
chlorides to the corresponding methyl esters. Aryl bromide (3.0 equiv.), butyryl
chloride (0.5 mmol), Pd2(dba)3 (5 mol%), Xantphos (10 mol%), DIPEA (3.0
equiv.), toluene (2.5 mL), 100 °C, 16 h. [b] GC yield using n-dodecane as
internal standard in parentheses. [c] Isolated with 5% of methyl benzoate.
[a] Yields refer to isolated products after in situ derivatization of the labile acid
chlorides to the corresponding methyl esters. Aryl triflate (3.0 equiv.), butyryl
chloride (0.5 mmol), Pd2(dba)3 (5 mol%), Xantphos (10 mol%), DIPEA (2.0
equiv.), toluene (2.5 mL), 100 °C, 16 h. [b] GC yield using n-dodecane as
internal standard in parentheses. [c] [Pd(allyl)Cl]2 (5 mol%) used instead of
Pd2(dba)3.
We next extended the palladium-catalyzed chlorocarbonylation to
another important class of electrophiles: aryl triflates. Even
though aryl triflates can be easily accessed from phenols, they
have rarely been used in carbonylation reactions and, to the best
Chlorocarbonylation of Aryl Iodides.
Subsequently,
we
turned
our
focus
to
the
of
our
knowledge,
have
never
been
used
in
chlorocarbonylation of aryl iodides. Recently, the CO-free
synthesis of aroyl chlorides from aryl iodides via a single-bond
metathesis with sacrificial aromatic acid chlorides had been
reported (Scheme 1b),[16] but the purification of the desired
product proved to be challenging in several cases due to the high-
boiling point and similar polarity of the by-products generated. We
envisioned that extension of the reaction developed in this study
to aryl iodides could overcome such purification issues by only
generating volatile propene as the sole by-product. Careful
optimization of the reaction parameters revealed that butyryl
chloride could be used in excess to drive the reaction to high
conversions in the case of aryl iodide substrates (see Supporting
Information, Tables S23-S34). This indicates that the oxidative
addition of the Pd-catalyst into the C(aryl)-I bond of the aryl iodide
starting material is more facile than the oxidative addition into the
C-Cl bond of the acid chloride product. Indeed, with 65 kcal/mol,
the bond energy of C(aryl)-I is weaker than the bond energy of C-
Cl (74 kcal/mol) in acyl chlorides.[15b,21b,23] Even though DIPEA as
base showed good results in the chlorocarbonylation, 1,4-
diazabicyclo[2.2.2]octane (DABCO) proved to be superior in this
case.[20]
chlorocarbonylation.[8a,22] After a slight re-optimization of the
reaction conditions (see Supporting Information, Tables S12-S22),
we found that a variety of aryl triflates could successfully undergo
the chlorocarbonylation reaction. As shown in Table 3, electron-
neutral (5a and 5e), electron-rich (5b, 5c, 5h and 5i) and electron-
deficient (5d, 5g, 5j and 5k) aryl triflates were tolerated under the
reaction conditions, giving the corresponding aroyl chlorides in
good yields. As in the case of aryl bromides, the presence of
ortho-substituents remains a limitation. Only a fluorine substituent
in the ortho-position was tolerated, giving 5f in a moderate 52%
yield, leaving the less hindered chloro-substituent untouched. An
L-tyrosine derivative, estrone, a coumarin derivative, and δ-
tocopherol were converted to their aryl triflate analogs and
subjected to the reaction conditions for the chlorocarbonylation.
The desired products were obtained in moderate to good yields
(5l, 5m, 5n and 5o), showing that the reaction can be used on a
more complex substrate.
We next examined the substrate scope for the
chlorocarbonylation of aryl iodides (Table 4). Similar to aryl
bromides and aryl triflates, a broad spectrum of functional groups
3
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RESEARCH ARTICLE
was tolerated under the reaction conditions. Electron-neutral (7a,
7i, and 7m), electron-rich (7b–d, 7h, 7o, 7p, 7q, 7r, 7t, and 7u)
and electron-deficient (7e, 7f, 7k, 7l, 7s, and 7v) substrates were
converted to the corresponding aroyl chlorides in good to
excellent yields. The substrate 1-bromo-4-iodobenzene (6g),
bearing both a bromide and iodide substituent, exclusively
provided product 7g in 79% yield, leaving the bromide substituent
unreacted. Therefore, this methodology should allow for a
sequential, orthogonal installation of multiple groups through
chemoselective chlorocarbonylation followed by cross-coupling
reactions.
chlorocarbonylation of aryl (pseudo)halides can be exploited to
give access to a broad spectrum of carbonyl-containing products.
The acyl chloride product can be used as a platform for further in
situ derivatization, thus enabling the one-pot synthesis of diverse
carbonyl products starting from aryl (pseudo)halides (Table 5).
1-Bromo-3,4-methylenedioxobenzene (1i) was selected as
substrate of choice to exemplify the derivatization, since it showed
good conversion to the corresponding acid chloride (Table 2). A
structurally more complex alcohol, (–)-menthol, and
a
cycloalkanethiol were first employed as nucleophiles and afforded
the desired ester 8a and thioester 8b in good yield. Reacting the
formed acyl chloride in situ with ammonia gave the corresponding
primary amide 8c. Weinreb-amide 8d could be obtained in 65%
yield, starting from aryl bromide 1i and reacting the in situ formed
acyl chloride with N,O-dimethylhydroxylamine. Derivatization with
other amines, such as morpholine and N-Boc-protected
piperazine gave amides 8e and 8f in good yields. Friedel-Crafts
acylation with N-Me-indole gave ketone 8g in 61% yield.
Interestingly, when sodium azide was added after the
chlorocarbonylation reaction, acyl azide 8h was obtained in 80%
yield.[25] To the best of our knowledge, this represents the first
azidocarbonylation starting from aryl bromides.[26] The
combination of our chlorocarbonylation with further catalytic
transformations in a one-pot process turned out to be feasible.
Aldehyde 8i was obtained in 59% yield after reacting the in situ
formed aroyl chloride with Bu3SnH in the presence of catalytic
amounts of indium trichloride.[27] Finally, one-pot Suzuki,
Sonogashira, and Kumada couplings with sp, sp2 and sp3 carbon
nucleophiles, respectively, enabled us to access the
corresponding ketones in good yields (8j, 8k and 8l).[28] Overall,
these results demonstrate the potential of this new protocol to
provide a unified strategy to access several important carbonyl
products without using exogeneous carbon monoxide.
Table 4. Palladium-catalyzed chlorocarbonylation of aryl iodides.[a]
Table 5. One-pot Synthesis of carbonyl-containing products.[a]
[a] Yields refer to isolated products after in situ derivatization of the labile acid
chlorides to the corresponding methyl esters. Aryl iodide (0.5 mmol), butyryl
chloride (10 equiv.), Pd2(dba)3 (5 mol%), Xantphos (10 mol%), DABCO (3.0
equiv), toluene (2.5 mL), 100 °C, 16 h. [b] GC yield using n-dodecane as internal
standard in parentheses. [c] o-xylene at 125 °C.
TMS-protected alkynes were left untouched in our reaction,
possibly because of steric hindrance (7n). Heterocycles were well
tolerated in the chlorocarbonylation of aryl iodides (7w). Product
7j with a fluorine substituent in ortho-position was isolated in
moderate yield (57%). The identity of 7j could be further confirmed
by single crystal X-ray analysis of the corresponding methyl
ester.[24]
One-Pot Synthesis of Carbonyl-Containing Products.
Acid chlorides exhibit high reactivity towards a great variety of
nucleophiles. Taking advantage of this property, the
[a] Yield of isolated products. For further information see SI. [b] Isolated with
10% benzamide. [c] [Pd(allyl)Cl]2 (5 mol%) used instead of Pd2(dba)3.
4
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Mechanistic Studies
In contrast to traditional carbonylation protocols, where a
conventional mechanism involving an electrophile and
nucleophile is assumed,[3a,i] our system relies on a reaction
between two electrophiles, butyryl chloride and an aryl halide.
Because such reactions are much less common, there are only
few mechanistic studies available.[19f,g,h,i] The attractive possibility
to contribute to this understudied area motivated us to study our
similar to related acyl complexes of Xantphos-ligated
palladium(II).[32] Long range correlation in the 1H-13C HMBC
spectrum between the carbon peak at  = 225.8 ppm and a proton
signal, identified as a CH2 group, confirms the identity of this
deshielded carbon signal as the carbonyl group of acyl complex
10. Unfortunately, this complex was found to be less stable than
the related complex reported by Skrydstrup[31] and rapidly
decomposed at room temperature. We could identify the
a
reaction using a combined experimental and theoretical approach. decomposition product of 10 as (Xantphos)PdCl2 by comparing
We started our investigation by performing a stoichiometric
experiment between bromobenzene, Pd2(dba)3, and Xantphos.
After four hours at 80 °C, it was possible to isolate a complex
which was confirmed to be the oxidative addition product 9 by X-
ray and NMR analysis (Scheme 2a).[20,29,30] The NMR resonances
of the complex are in accordance with literature values for similar
complexes.[29]
Next, we turned our attention on the reaction of butyryl
chloride and Pd(0). Pioneering work on the oxidative addition of
Pd(0) complexes into aliphatic acid chlorides was reported by
Skrydstrup using P(t-Bu)3 as ligand.[10b,31] Gratifyingly, we could
synthesize the related oxidative addition complex 10 bearing a
Xantphos ligand. A singlet peak at 2.1 ppm was observed by
31P{1H} NMR spectroscopy, which is in accordance to shifts
previously reported for other acyl complexes of Xantphos-ligated
palladium(II).[5a,32] Furthermore, a very deshielded carbon ( =
the spectroscopic data to the data of an authentic sample.
In order to further investigate our chlorocarbonylation
reaction, we performed in situ NMR analysis under catalytic
conditions. Within the first 30 minutes, two new resonances
appeared in the 31P{1H} NMR spectrum which had very similar
shifts when compared to the shifts of complexes 9 and 10. These
two peaks remained visible over the course of the reaction and
therefore possibly correspond to the resting states of the catalytic
cycle.[20] Taking into account the difference in temperature at
which the spectra were recorded, these two complexes could
correspond to compounds 9 and 10. DFT calculations of the
reaction mechanism (Figure 1; vide infra) support the assignment
of complex 10 as a resting state of the reaction and propose
(Xantphos)Pd(benzoyl)(Br)
(complex
J)
instead
of
(Xantphos)Pd(Ph)(Br) (9) as the second resting state.
Considering that (Xantphos)Pd(benzoyl)(X) (X= Cl or Br) and
225.8 ppm) was observed as a triplet peak in the 13C{1H} spectrum. complex 9 have very similar 31P{1H} NMR shifts,[5a,32] no definite
conclusions can be drawn about the identity of the complexes
observed by 31P{1H} NMR spectroscopy of the catalytic reaction
(Scheme 2c).
Similar to previous reports,[10b,31] we envisaged that carbon
monoxide release from complex 10 and subsequent β-hydride
elimination of the propyl fragment could lead to formation of a
(Xantphos)Pd(H)(Cl) species. The latter could be readily
transformed to an active Pd(0) species by reductive elimination in
the presence of DIPEA. This Pd(0) species could then undergo
oxidative addition with the aryl halide. As the time scale of these
steps limited an in situ spectroscopic investigation, we decided to
test our hypothesis of CO release and β-hydride elimination by
other means. By using a gas-tight syringe, the gases present in
the headspace of the reaction could be analyzed by GC-MS.
Propene was unambiguously identified by comparison of the
mass spectrum with an independent reference spectrum
(Scheme 3a).[20] The formation of propene was further confirmed
by 1H-NMR spectroscopy with signals at  = 5.67, 4.96, and 4.90
ppm, matching data reported in literature.[20,31]
Scheme 2. a) Reaction of bromobenzene with Pd2(dba)3 and Xantphos. Crystal
structure of the oxidative addition complex 9. b) Reaction of butyryl chloride with
with Pd2(dba)3 and Xantphos. c) 31P{1H} NMR spectra of both oxidative addition
complexes 9 and 10 (room temperature) in comparison with a 31P{1H} NMR
spectrum of the reaction mixture (100 °C).
Scheme 3. a) Detection of propene by GC-MS headspace analysis. b)
We assigned this peak to the carbonyl carbon of 10 that
Detection of carbon monoxide by two-chamber aminocarbonylation.
couples to the ligand phosphorous atoms. Its chemical shift is very
5
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10.1002/anie.202005891
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RESEARCH ARTICLE
modelled with the def2tzvp basis set.[40,41] The corresponding ECP
was used for palladium. Structures were visualized with
CYLview.[45]
Since carbon monoxide cannot be detected by our GC-MS
detector, we investigated the potential formation of free carbon
monoxide by other means. When running the reaction of
bromobenzene in an open system, the yield of benzoyl chloride
drops to 38%, compared to 83% yield in a closed system.[20] This
indicates that in situ generated free, unbound CO might escape
the reaction medium during the process. To further support our
hypothesis of carbon monoxide release, the reaction depicted in
Scheme 3b was conducted in a sealed two-chamber system.[10b]
One chamber was loaded with the optimized conditions for the
chlorocarbonylation of aryl bromides discussed earlier, omitting
bromobenzene. The other chamber was loaded with 4-iodo-1,2-
dimethoxybenzene (6q) and conditions developed for the
aminocarbonylation of aryl halides.[10b] The expected
aminocarbonylation product 12 was isolated in 91% yield,
confirming that CO is generated in situ from our catalytic
conditions.
We began our investigation by analyzing the activation of butyryl
chloride (2) by Pd(Xantphos) (A) (Figure 1). Based on our
experimental results and previous reports, it is likely that the
reaction commences by the oxidative addition of the palladium(0)
complex A into the C-Cl bond of butyryl chloride (2).[10b,31] This
process has a low computed energy barrier of 4.8 kcal/mol (TS1).
The resulting complex B is 12.1 kcal/mol more stable than the
combination of Pd(Xantphos) (A) and butyryl chloride (2). Next,
as suggested by experimental evidence, the energy pathway for
the de-insertion of carbon monoxide and subsequent propene
formation was investigated. The CO de-insertion step is predicted
to have an energy barrier of 22.4 kcal/mol (TS2). From complex
C, in which a propyl, chloride, and carbonyl ligand are bound to
Pd(Xantphos), two possible pathways for the extrusion of propene
were analyzed. The first option is the direct β-hydride elimination
from complex C to give rise to a carbonylated palladium hydride
species. This pathway could be ruled out by the high-energy
transition state (30.1 kcal/mol, TS3) compared to alternative
pathways. This high activation barrier presumably arises from the
coordinatively saturated nature of the palladium species. In
contrast, CO loss from C is only 1.7 kcal/mol uphill, and the
subsequent β-hydride elimination from the square-planar complex
D is more easily accessible with a lower energy barrier of 17.9
kcal/mol (TS4). Loss of propene gives rise to Pd(Xantphos)(H)(Cl)
(E), which undergoes reductive elimination of HCl in the presence
of base (TS5).
Computational Studies
In order to study the feasibility of different mechanistic
pathways, we performed extensive computational studies based
on density functional theory (DFT). The transformation of
bromobenzene to benzoyl chloride was used as a model for the
reaction of aryl bromide substrates. All calculations were
conducted using the Gaussian09 suite of programs.[20,33] The
keyword integral(grid=ultrafine) was used in all calculations to
limit grid-based errors.[34] Geometries were optimized at the PBE
level of theory[35,36] including Grimme dispersion correction (D3)
with Becke-Johnson damping[37,38] and the SMD solvent model for
toluene.[39] Palladium was modelled with the def2tzvp basis set
and ECP.[40,41] All other atoms were modelled with the def2svp
basis set. Single point energies and thermochemical corrections
were calculated with the PBE0 functional[35,36,42,43] including
Grimme dispersion correction (D3) with Becke-Johnson
damping,[37,38] the SMD solvent model for toluene,[39] and thermal
correction to 373 K. The PBE0 functional was chosen due to its
excellent performance in benchmarking studies.[44] All atoms were
The re-formed Pd(Xantphos) complex A can readily trap the
released
carbon
monoxide.
The
resulting
complex
Pd(Xantphos)(CO) (F) is predicted to be 18.3 kcal/mol more
stable than the combination of Pd(Xantphos) (A) and free CO.
The activation energy for the oxidative addition of bromobenzene
(1a) to F was calculated to be much higher in energy (TS7; 34.1
kcal/mol) than to A (TS6 via complex G; 12.3 kcal/mol). The
oxidative addition of bromobenzene should therefore
preferentially occur with the non-carbonylated complex A.
Figure 1. Energy profile for the palladium-catalyzed formation of benzoyl chloride (3a) from butyryl chloride (2) and bromobenzene (1a) at the
PBE0-D3(BJ)/SMD(PhMe)-def2tzvp//PBE-D3(BJ)/SMD(PhMe)-def2svp-def2tzvp(Pd) level of theory. The optimized geometries of the transition states TS3, TS4,
TS9, and TS10 are depicted. Hydrogen atoms except for hydrides are omitted for clarity.
6
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10.1002/anie.202005891
Angewandte Chemie International Edition
RESEARCH ARTICLE
Although the carbonyl complex F is unlikely to be a
productive intermediate in the catalytic reaction, temporary
trapping of free CO by Pd(Xantphos) to form complex F and
potentially [Pd(Xantphos)(CO)2][26b] might explain why the
reaction of bromobenzene (1a) still gave 38% yield of benzoyl
chloride (3a) product in an open reaction system (vide supra).
Complex H can trap carbon monoxide to form the penta-
coordinate complex I. Migratory insertion of CO into the Pd-Ph
bond of I (TS9) has a low energy barrier of 5.2 kcal/mol and is
16.3 kcal/mol downhill (complex J). The energy barrier for the
subsequent reductive elimination of acyl halide was found to be
slightly lower from chlorido complex K than bromido complex J.[20]
This suggests that complex J preferentially undergoes halide
exchange with the hydrochloride of DIPEA to form complex K.
The subsequent reductive elimination of benzoyl chloride (1a) has
an energy barrier of 21.2 kcal/mol and leads to the regeneration
of palladium(0) complex A, closing the catalytic cycle. The halide
exchange from bromide to chloride was also evaluated for earlier
(from complex H) and later stages (from free benzoyl bromide) of
the reaction.[20] The resulting energy profiles for the formation of
the acyl chloride product are only slightly less favorable than the
pathway described above and also accessible. It is therefore likely
that a mixture of these mechanisms is operating in the experiment
with the depicted energy profile as the main pathway.
Recently, we reported the synthesis of aroyl chlorides from
aryl iodides, through a functional group metathesis pathway,
using a similar catalytic system to the one employed in this study
(Scheme 2b).[16a] Mechanistic experiments showed that the
reaction likely proceeds via C-P reductive elimination with the
Xantphos ligands to form phosphonium ions. While investigating
the scope of the reaction developed in this study, methyl benzoate
was indeed observed as a minor side product in the reaction of
certain substrates (e. g. 3k). Its formation could be explained by
scrambling of the Xantphos-phenyl groups with the aryl group of
the substrate. We therefore investigated if the main mechanistic
pathway involves a similar C-P reductive elimination step as in our
previous study. If the reaction proceeded through a phosphonium
ion, complex H would have to undergo C-P reductive elimination
(TS8). The energy barrier for this process was calculated to be
24.9 kcal/mol (Figure 1). This pathway is therefore accessible, but
much less favorable than the one depicted in Figure 1. This
makes it very unlikely that the main mechanistic pathway of this
new reaction proceeds through a C-P reductive elimination
mechanism. We were curious to understand whether the
availability of free, unbound CO in the reaction mixture might be
the origin of the different pathways that are observed for this
reaction and our previously reported single-bond metathesis
reaction.[16a] To test whether free CO is generated under the
conditions employed in the latter protocol[16a], we used a similar
two-chamber system as depicted in Scheme 3b.[20] Only traces of
carbonylation were observed in the second reaction chamber.
This supports our hypothesis that the availability of free CO in the
reaction leads to the difference in reaction pathways observed
between this new reaction and our previously-reported single-
bond metathesis reaction.[16a] The reason why aroyl chlorides do
not generate free CO in their reaction with the Pd(Xantphos)
system while aliphatic acyl chlorides do, is unclear at this stage
and under further investigation.
With the results of our mechanistic experiments and the
computational studies, we propose
a mechanism for the
chlorocarbonylation of aryl halides (Figure 2). In the right cycle of
the mechanism, Xantphos-ligated Pd(0) undergoes oxidative
addition into the carbon-chlorine bond of butyryl chloride (2) to
give intermediate I. This can then de-insert and subsequently
release carbon monoxide to give intermediates II and III,
respectively. A free coordination site at the palladium center is
created to facilitate β-hydride elimination and afford
(Xantphos)Pd(H)(Cl) complex IV. This can then undergo base-
induced reductive elimination to regenerate the Pd(0) species. On
the left side of the catalytic cycle, aryl bromide 1a can undergo
oxidative addition to (Xantphos)Pd(0) to give literature-known
complex V.[29] This complex can then bind free carbon monoxide
present in the reaction mixture to give complex VI. After CO
insertion to afford VII, nucleophilic displacement of the bromine
ligand with chloride takes place to give complex VIII. This can then
reductively eliminate to give benzoyl chloride (3) and close the
catalytic cycle.
Figure 2. Proposed mechanism for the chlorocarbonylation of aryl halides based on experimental and computational studies.
7
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10.1002/anie.202005891
Angewandte Chemie International Edition
RESEARCH ARTICLE
Wu, Chem. Rev. 2019, 119, 2090 – 2127. c) M. Beller, Catalytic
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Conclusion
In summary, we have developed a new palladium-catalyzed
chlorocarbonylation of aryl (pseudo)halides which uses butyryl
chloride as in situ source of both CO and Cl. This reaction gives
access to a broad variety of acid chlorides, starting from
commercially available or easily accessible aryl bromides, iodides,
and triflates. Inexpensive butyryl chloride as a donor not only
addresses the safety issues encountered with the use of
exogenous carbon monoxide, but also overcomes the need for
specialized equipment, such as high-pressure or two-chamber
reactors. A single catalytic system can be used to synthesize a
broad range of carbonyl-containing products in a one-pot two-step
procedure which normally requires different catalytic systems and
pressurized CO for their synthesis.
In-depth experimental and computational studies of the reaction
mechanism point towards in situ generation of CO from butyryl
chloride and its incorporation into the aryl halide. In contrast to our
previously reported functional group metathesis between aryl
iodides and aroyl chlorides, the pathway via reductive elimination
with the Xantphos ligand is kinetically unfavorable when
employing aliphatic acid chlorides as reagents.
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Experimental and computational details, full reference 33, and
compound characterization are given in the supporting
information.
Acknowledgements
This project received funding from the European Research
Council under the European Union's Horizon 2020 research and
innovation program (Shuttle Cat, Project ID:757608). ETH Zürich
is gratefully acknowledged for financial support. We thank the
NMR service, the Molecular and Biomolecular Analysis Service
(MoBiAS), and the Small Molecule Crystallography Center (Dr.
Nils Trapp, SMoCC) of ETH Zürich for technical assistance. P. B.
thanks the FCI for a scholarship. We thank Tristan Delcaillau,
Yong Ho Lee, Michael Bogdos, and Marius Lutz for fruitful
discussions.
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Keywords: chlorocarbonylation • palladium • shuttle catalysis •
reaction mechanism • computations
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9
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RESEARCH ARTICLE
Entry for the Table of Contents
10
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